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15  structures 3824  species 1  interaction 4602  sequences 22  architectures

Family: HEM4 (PF02602)

Summary: Uroporphyrinogen-III synthase HemD

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This is the Wikipedia entry entitled "Uroporphyrinogen III synthase". More...

Uroporphyrinogen III synthase Edit Wikipedia article

Uroporphyrinogen-III synthase
Identifiers
EC number 4.2.1.75
CAS number 37340-55-9
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Uroporphyrinogen III synthase
Identifiers
Symbol UROS
Entrez 7390
HUGO 12592
OMIM 606938
RefSeq NM_000375
UniProt P10746
Other data
Locus Chr. 10 q25.2-26.3
Uroporphyrinogen-III synthase HemD
PDB 1wd7 EBI.jpg
crystal structure of uroporphyrinogen iii synthase from an extremely thermophilic bacterium thermus thermophilus hb8 (wild type, native, form-2 crystal)
Identifiers
Symbol HEM4
Pfam PF02602
InterPro IPR003754
SCOP 1jr2
SUPERFAMILY 1jr2

Uroporphyrinogen III synthase EC 4.2.1.75 is an enzyme involved in the metabolism of the cyclic tetrapyrrole compound porphyrin. It is involved in the conversion of hydroxymethyl bilane into uroporphyrinogen III. This enzyme catalyses the inversion of the final pyrrole unit (ring D) of the linear tetrapyrrole molecule, linking it to the first pyrrole unit (ring A), thereby generating a large macrocyclic structure, uroporphyrinogen III.[1] The enzyme folds into two alpha/beta domains connected by a beta-ladder, the active site being located between the two domains.[2]

Heme synthesis—note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow)

Pathology[edit]

A deficiency is associated with Gunther's disease, also known as congenital erythropoietic porphyria (CEP). This is an autosomal recessive inborn error of metabolism that results from the markedly deficient activity of uroporphyrinogen III synthase .[3]

External links[edit]

References[edit]

  1. ^ Raux E, Schubert HL, Warren MJ (December 2000). "Biosynthesis of cobalamin (vitamin B12): a bacterial conundrum". Cell. Mol. Life Sci. 57 (13-14): 1880–93. doi:10.1007/PL00000670. PMID 11215515. 
  2. ^ Mathews MA, Schubert HL, Whitby FG, Alexander KJ, Schadick K, Bergonia HA, Phillips JD, Hill CP (November 2001). "Crystal structure of human uroporphyrinogen III synthase". EMBO J. 20 (21): 5832–9. doi:10.1093/emboj/20.21.5832. PMC 125291. PMID 11689424. 
  3. ^ To-Figueras J, Badenas C, Mascaro JM, Madrigal I, Merino A, Bastida P, Lecha M, Herrero C (2007). "Study of the genotype-phenotype relationship in four cases of congenital erythropoietic porphyria". Blood Cells Mol. Dis. 38 (3): 242–6. doi:10.1016/j.bcmd.2006.12.001. PMID 17270473. 

This article incorporates text from the public domain Pfam and InterPro IPR003754

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Uroporphyrinogen-III synthase HemD Provide feedback

This family consists of uroporphyrinogen-III synthase HemD EC:4.2.1.75 also known as Hydroxymethylbilane hydrolyase (cyclizing) from eukaryotes, bacteria and archaea. This enzyme catalyses the reaction: Hydroxymethylbilane <=> uroporphyrinogen-III + H(2)O. Some members of this family are multi-functional proteins possessing other enzyme activities related to porphyrin biosynthesis, such as Q59294 with PF00590 however the aligned region corresponds with the uroporphyrinogen-III synthase EC:4.2.1.75 activity only. Uroporphyrinogen-III synthase is the fourth enzyme in the heme pathway [2]. Mutant forms of the Uroporphyrinogen-III synthase gene cause congenital erythropoietic porphyria in humans a recessive inborn error of metabolism also known as Gunther disease [1].

Literature references

  1. Xu W, Astrin KH, Desnick RJ; , Hum Mutat 1996;7:187-192.: Molecular basis of congenital erythropoietic porphyria: mutations in the human uroporphyrinogen III synthase gene. PUBMED:8829650 EPMC:8829650

  2. Amillet JM, Labbe-Bois R; , Yeast 1995;11:419-424.: Isolation of the gene HEM4 encoding uroporphyrinogen III synthase in Saccharomyces cerevisiae. PUBMED:7597845 EPMC:7597845


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR003754

Tetrapyrroles are large macrocyclic compounds derived from a common biosynthetic pathway [PUBMED:16564539]. The end-product, uroporphyrinogen III, is used to synthesise a number of important molecules, including vitamin B12, haem, sirohaem, chlorophyll, coenzyme F430 and phytochromobilin [PUBMED:17227226].

  • The first stage in tetrapyrrole synthesis is the synthesis of 5-aminoaevulinic acid ALA via two possible routes: (1) condensation of succinyl CoA and glycine (C4 pathway) using ALA synthase (EC), or (2) decarboxylation of glutamate (C5 pathway) via three different enzymes, glutamyl-tRNA synthetase (EC) to charge a tRNA with glutamate, glutamyl-tRNA reductase (EC) to reduce glutamyl-tRNA to glutamate-1-semialdehyde (GSA), and GSA aminotransferase (EC) to catalyse a transamination reaction to produce ALA.

  • The second stage is to convert ALA to uroporphyrinogen III, the first macrocyclic tetrapyrrolic structure in the pathway. This is achieved by the action of three enzymes in one common pathway: porphobilinogen (PBG) synthase (or ALA dehydratase, EC) to condense two ALA molecules to generate porphobilinogen; hydroxymethylbilane synthase (or PBG deaminase, EC) to polymerise four PBG molecules into preuroporphyrinogen (tetrapyrrole structure); and uroporphyrinogen III synthase (EC) to link two pyrrole units together (rings A and D) to yield uroporphyrinogen III.

  • Uroporphyrinogen III is the first branch point of the pathway. To synthesise cobalamin (vitamin B12), sirohaem, and coenzyme F430, uroporphyrinogen III needs to be converted into precorrin-2 by the action of uroporphyrinogen III methyltransferase (EC). To synthesise haem and chlorophyll, uroporphyrinogen III needs to be decarboxylated into coproporphyrinogen III by the action of uroporphyrinogen III decarboxylase (EC) [PUBMED:11215515].

This entry represents uroporphyrinogen III synthase (EC) which functions during the second stage of tetrapyrrole biosynthesis. This enzyme catalyses the inversion of the final pyrrole unit (ring D) of the linear tetrapyrrole molecule, linking it to the first pyrrole unit (ring A), thereby generating a large macrocyclic structure called uroporphyrinogen III [PUBMED:11215515]. The enzyme folds into two alpha/beta domains connected by a beta-ladder, the active site being located between the two domains [PUBMED:11689424]. Congenital erythropoietic porphyria (CEP) is an autosomal recessive inborn error of metabolism that results from the markedly deficient activity of uroporphyrinogen III synthase [PUBMED:17270473].

Gene Ontology

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Domain organisation

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Alignments

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(137)
Full
(4602)
Representative proteomes NCBI
(3545)
Meta
(2287)
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(418)
RP35
(849)
RP55
(1111)
RP75
(1293)
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  Seed
(137)
Full
(4602)
Representative proteomes NCBI
(3545)
Meta
(2287)
RP15
(418)
RP35
(849)
RP55
(1111)
RP75
(1293)
Alignment:
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  Seed
(137)
Full
(4602)
Representative proteomes NCBI
(3545)
Meta
(2287)
RP15
(418)
RP35
(849)
RP55
(1111)
RP75
(1293)
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Curation and family details

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Seed source: COG1587
Previous IDs: none
Type: Family
Author: Bashton M, Bateman A
Number in seed: 137
Number in full: 4602
Average length of the domain: 221.40 aa
Average identity of full alignment: 21 %
Average coverage of the sequence by the domain: 70.07 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.5 27.5
Trusted cut-off 27.8 27.5
Noise cut-off 27.2 27.4
Model length: 231
Family (HMM) version: 10
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Interactions

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HEM4

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the HEM4 domain has been found. There are 15 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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